UCLA

The 1,3-dipolar cycloaddition and Diels-Alder reaction have been applied countless times in synthetic organic chemistry, materials chemistry, and now chemical biology. The stereoselectivity and rapid kinetics have been harnessed to develop the field of bioorthogonal chemistry. In this thesis, the origins of the rapid kinetics and exo-facial selectivity of norbornene was explained and extended to a series of pyramidalized norbornenes and sesquinorbornenes. These were studied using DFT (Density Functional Theory) at the M06-2X/6-311G(d,p) level along with other computational models. The transition structures and activation barriers for these reactions were calculated. An analysis of the calculations revealed that distortion energy is greatly responsible for the observed stereoselectivity, and a simple relationship was derived between pyramidalization and activation barriers. We propose the term, distortion-accelerated, to describe why the reactions are fast, rather than strain-promoted, because the alkenes release most of their strain energy before the transition state.

In a second portion of the thesis I applied the concept of distortion-acceleration to a recently discovered mutually orthogonal 1,3-dipolar cycloaddition and an inverse-demand Diels-Alder reaction. Mutually orthogonal reactions were used in the literature to selectively label two different cancer cells simultaneously. We explained this selectivity difference using modern computational methodology. DFT was used for this computational investigation at the M06-2X/6-311+G(d,p) level and the Polarizable Continuum Model (PCM) was used to correct for solvation effects. It was found that distortion energy, LUMO energies, and steric effects are responsible for the observed selectivity. General rules were developed to easily predict new mutually orthogonal pairs once their bioorthogonality is known.